CN115702888B

CN115702888B - Oxycodone hydrochloride osmotic pump sustained release tablet and preparation method thereof

Info

Publication number: CN115702888B
Application number: CN202110928594.2A
Authority: CN
Inventors: 陈军; 徐磊; 苗青; 何杰; 刘锦平; 王长丹
Original assignee: Hefei Lifeon Pharmaceutical Co ltd
Current assignee: Hefei Lifeon Pharmaceutical Co ltd
Priority date: 2021-08-13
Filing date: 2021-08-13
Publication date: 2024-05-28
Anticipated expiration: 2041-08-13
Also published as: CN115702888A

Abstract

The invention relates to the field of pharmaceutical preparations, and in particular provides an abuse-proof oxycodone hydrochloride sustained release tablet and a preparation method thereof, wherein the sustained release tablet comprises a tablet core, a controlled release film coating and a film coating, wherein the tablet core comprises 1% -60% of oxycodone hydrochloride, 25% -95% of release regulator, 0% -10% of adhesive and 0.1% -5% of lubricant by weight of the tablet core. The sustained-release tablet preparation is applied to the abuse prevention field through a controlled-release film coating technology, is difficult to damage, is difficult to extract oxycodone hydrochloride in the preparation, is more beneficial to preventing abuse of opioid drugs, is stable in drug release, realizes a better in-vivo pharmacokinetic in-vitro release curve, and can reduce the use amount of the drugs. The preparation method of the sustained-release tablet is simple and feasible in process, creatively uses a process route of coating and curing, and solves the technical defect of curing the tablet.

Description

Oxycodone hydrochloride osmotic pump sustained release tablet and preparation method thereof

Technical Field

The invention relates to the field of pharmaceutical preparations, in particular to an abuse-proof oxycodone hydrochloride sustained release tablet and a preparation method thereof.

Background

Oxycodone hydrochloride is an anesthetic drug, is a semisynthetic opioid extracted from alkaloid thebaine, belongs to a strong opioid, is mainly used for first-line treatment of moderately severe pain, is first cancer pain treatment, and is later developed to chronic non-cancer pain treatment. The drug is first made in Germany in 1917, has been clinically applied for more than 80 years as a powerful analgesic, is a variety listed in the United nations' single convention for narcotics in 1961, and is also classified into the narcotics control range in China.

The general formulation of oxycodone hydrochloride has two major disadvantages: 1. oxycodone is a complete agonist of opioid receptors and has a similar abuse liability to morphine, which is an narcotic analgesic drug, and as with morphine and other opioid drugs for analgesia, there is a potential for abuse. 2. Half-life is 3-4 hours, so that about 4-6 times a day are required.

The commodity name isOxycodone hydrochloride sustained release tablets (developed by Purdue) have been approved by the FDA for commercialization. They are made by using matrix sustained release tablet technique, and the hydrophilic gel layer formed by matrix in water is used to control the drug release. From the patent of the products (US 8894988, US 7674800), the specification emphasizes the action of the molecular weight and content of polyoxyethylene in the formulation prescription in the formulation, and the polyoxyethylene can be melted in the heating process and form a high-hardness state after being cooled again, so that the polyoxyethylene has good capability of preventing physical damage and chemical damage. In the specification, the curing process adopts tablet cores to be directly heated and cured, magnesium stearate is scattered as an anti-adhesive agent in the curing process, and coating is carried out after curing is finished. The defect of this design is that the tablet core is easy to generate sticking and deformation in the curing process, and the operation of scattering magnesium stearate easily causes uneven magnesium stearate content of each tablet, thereby affecting the quality of medicines. The method is also unfavorable for mass production and affects the production efficiency.

Patent CN 102657630A discloses a solid oral extended release pharmaceutical dosage form comprising an extended release matrix formulation comprising a composition containing at least oxycodone hydrochloride and at least about 80wt% of polyethylene oxide having a molecular weight of at least 100 tens of thousands. However, this patent does not prevent abuse of the drug by the oral route and has the disadvantage of a minimum drug administration time of 12 hours. According to the invention, on the basis of keeping the polyoxyethylene matrix, a layer of controlled release film coating is added, so that not only can the high hardness state of the original tablet core matrix be kept, but also a damage-proof barrier can be added for the tablet core, the cracking force of the tablet core is greatly improved, and the difficulty of damaging the tablet core is also greater. The controlled release film coating can regulate the release of the drug at the same time, so that the release is smoother, and for opioid drugs, the inability to release rapidly means the inability to abuse by the oral route. Thus the present invention can prevent abuse of the oral route to a greater extent.

Li Fang A brief introduction of innovation result of opioid abuse prevention technology discloses that polyethylene oxide and hydroxypropyl methylcellulose are added into oxycodone hydrochloride sustained-release tablets to enable the tablets to be gelatinous in a solvent so as to prevent raw medicines from being used for intravenous injection after being extracted by the solvent. Patent CN 111465396A discloses a solid oral slow-release pharmaceutical dosage form of morphine sulfate, comprising morphine sulfate, 55% -95% of polyethylene oxide with molecular weight of 60-300 ten thousand, 0.1% -5% of lubricant preferably magnesium stearate, and 0.1% -2.5% of glidant preferably colloidal silicon dioxide. However, this document, patent, still fails to address drug abuse via the oral route.

Therefore, the prior art needs to be further improved, so that the oxycodone hydrochloride sustained release tablet has better abuse prevention and sustained release effects, can effectively solve the problem of preventing the abuse of drugs in an oral way, can reduce the use frequency of the drugs, improves the release behavior of the drugs, has better sustained release effects, and further ensures that the oxycodone hydrochloride is used more safely and effectively.

Disclosure of Invention

Aiming at the technical problems, the invention provides an improved oxycodone hydrochloride sustained release tablet preparation, which is prepared by performing controlled release film coating and film coating on a sustained release tablet core and then performing high-temperature curing to obtain an abuse-proof oxycodone hydrochloride sustained release tablet with good quality, and particularly provides an oxycodone hydrochloride sustained release tablet and a preparation method thereof.

The invention provides an oxycodone hydrochloride sustained release tablet which comprises a tablet core, a controlled release film coating and a film coating, wherein the tablet core comprises the following components in percentage by weight:

The weight gain of the controlled release film coating is 1% -20% of the weight of the tablet core; the weight gain of the film coating is 1-15% of the weight of the tablet core.

In the present invention, as one embodiment, the release modifier is used in an amount of 50% to 95%, preferably 80% to 95% by weight of the tablet core.

As one embodiment, the release modifier of the present invention is selected from polyoxyethylene, wherein the polyoxyethylene is polyoxyethylene having a molecular weight of 10 ten thousand or more, preferably polyoxyethylene having a molecular weight of 10 ten thousand to 700 ten thousand, or a combination of polyoxyethylene having different molecular weights among the above 10 ten thousand to 700 ten thousand;

Illustrative examples of polyoxyethylene employed in the present invention include, but are not limited to, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, or 700 polyoxyethylene of different molecular weights.

As one embodiment, when polyoxyethylene of a single molecular weight is used, the release modifier of the present invention is selected from polyoxyethylene of 100 to 700 ppm, preferably polyoxyethylene of 200 to 700 ppm, more preferably polyoxyethylene of 400 to 700 ppm, still more preferably polyoxyethylene of 400 to 600 ppm; as one embodiment, the release modifier of the present invention is preferably polyoxyethylene having a molecular weight of 400 ten thousand, 500 ten thousand, 600 ten thousand or 700 ten thousand, and most preferably polyoxyethylene having a molecular weight of 500 ten thousand.

When a composition of polyoxyethylene having different molecular weights is used as one of the embodiments, it may be a combination of polyoxyethylene having a molecular weight of 10 to 100 tens of thousands, preferably 10 to 50 tens of thousands, with polyoxyethylene having a molecular weight of 200 to 700 tens of thousands, preferably 400 to 700 tens of thousands, further preferably 400 to 600 tens of thousands, and most preferably 500 tens of thousands; as one of the embodiments, wherein in the polyoxyethylene compositions of different molecular weights, polyoxyethylene of 200 to 700 tens of thousands of molecular weights, preferably polyoxyethylene of 400 to 700 tens of thousands, further preferably polyoxyethylene of 400 to 600 tens of thousands of molecular weights, and most preferably polyoxyethylene of 500 tens of thousands of molecular weights account for not less than 15%, preferably less than 50%, more preferably not less than 80%.

As an example of an embodiment, using a composition of polyoxyethylene of different molecular weights, the release modifier of the present invention is a combination of 10 ten thousand molecular weight and 500 ten thousand molecular weight polyoxyethylene, wherein the weight part ratio of 10 ten thousand molecular weight to 500 ten thousand molecular weight polyoxyethylene is 15:115 to 110:20; preferably 15:115 to 80:50; as an exemplary illustration, for example, 15:115, 45:85, 80:50, or 110:20.

As one embodiment, the polyoxyethylene of the present invention is selected from polyoxyethylene having a molecular weight of 200 to 700 ten thousand or more; as a still further embodiment of the present invention, the polyoxyethylene is polyoxyethylene having a molecular weight of 400 to 700 ten thousand. The source of the polyoxyethylene according to the present invention is not limited at all, and may be commercially available or may be prepared by one skilled in the art in combination with the prior art.

As one embodiment, the release modifier (polyoxyethylene) of the present invention is used in an amount of 40％、41％、42％、43％、44％、45％、46％、47％、48％、49％、50％、51％、52％、53％、54％、55％、56％、57％、58％、59％、60％、61％、62％、63％、64％、65％、66％、67％、68％、69％、70％、71％、72％、73％、74％、75％、76％、77％、78％、79％、80％、81％、82％、83％、84％、85％、86％、87％、88％、89％ or 90% by weight of the core, illustrative examples of which include, but are not limited to. As one embodiment, the polyoxyethylene is preferably used in an amount of 50% to 95% by weight of the tablet core; more preferably 80 to 95%.

In the present invention, as one embodiment, the binder is preferably used in an amount of 2% to 8%, more preferably 5% to 8%, by weight of the tablet core, such as 2%, 3%, 4%, 5%, 6%, 7% or 8%, by way of example.

In the present invention, as one embodiment, the binder includes, but is not limited to, starch, dextrin, gelatin, polyethylene glycol, methylcellulose, hydroxypropyl cellulose, povidone, hydroxypropyl methylcellulose, or a combination of two or more thereof, preferably hydroxypropyl cellulose.

In the present invention, when the binder of the present invention is hydroxypropyl cellulose, the hydroxypropyl cellulose may be any of various types of hydroxypropyl cellulose in the art, and the source thereof is not limited at all, and may be commercially available or may be prepared by one skilled in the art according to the descriptions of the prior art. As one of the embodiments of the present invention, the binder is hydroxypropylcellulose HXF (Ashland) in an amount of 0% to 10%, preferably 2% to 8%, more preferably 5% to 8%, by weight of the tablet core, as exemplified by 2%, 3%, 4%, 5%, 6%, 7% or 8%.

As one of the embodiments of the present invention, the binder may also be hypromellose or povidone.

In the present invention, as one embodiment, the lubricant is used in an amount of 0.1% to 4%, preferably 0.2% to 2% by weight of the tablet core.

As one of the embodiments of the present invention, the lubricant is magnesium stearate, silica gel micropowder, talcum powder, sodium lauryl sulfate, magnesium lauryl sulfate, or a combination of two or more thereof; magnesium stearate is preferred.

In the present invention, as one embodiment, the weight gain of the controlled release film coating is 1.0% to 20.0%, preferably 3.0% to 12.0%, more preferably 6.0% to 10.0%, by way of example, such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% of the weight of the tablet core.

In the present invention, as one embodiment, the controlled release film coating comprises a film forming material, a porogen, and a coating solvent.

In the present invention, as one embodiment, the film-forming material is cellulose acetate, ethyl cellulose, ethylene-vinyl acetate copolymer, methacrylate copolymer, or a combination of two or more thereof, preferably cellulose acetate, in an amount of 1% to 30%, preferably 1.0% to 10.0%, more preferably 1.0% to 6.0%, by weight of the controlled release film coating, such as 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%, by way of example.

In the present invention, as one embodiment, the pore-forming agent is polyethylene glycol (PEG 4000), povidone, hypromellose, polysorbate, sorbitan fatty acid ester, polyvinyl alcohol, lactose, or a combination of two or more thereof, preferably polyethylene glycol (PEG 4000), and the amount is 0.1% to 20%, preferably 0.5% to 15.0%, more preferably 1.0% to 10.0%, still more preferably 0.5% to 5.0%, still more preferably 1.0% to 4.0%, as exemplified, such as 1%, 2%, 3% or 4% by weight of the controlled release film coating.

In the present invention, as one embodiment, the controlled release film coating solvent is selected from acetone, ethanol, or a combination of acetone and methanol, or a mixture of acetone and water, or a mixture of dichloromethane and ethanol, preferably acetone, in an amount of 50% to 95%, preferably 80.0% to 95.0% by weight of the controlled release film coating.

As one of the embodiments of the invention, the oxycodone hydrochloride sustained release tablet also comprises a controlled release film coating which has the function of controlling the stable release of the drug and is insoluble in water. The high-temperature curing agent has good thermal stability, does not change quality in the high-temperature curing process, and can protect the tablet core from deformation. After coating, hard shell is formed to protect the tablet core, so that the tablet core is difficult to be destroyed by external force (physical and chemical means), and oxycodone hydrochloride is extracted.

In the present invention, the weight gain of the film coating is 1.0% to 8.0%, preferably 3.0% to 6.0%, more preferably 3.0% to 5.0%, by way of example, such as 1%, 2%, 3%, 4%, 5%, 6%, 7% or 8% of the weight of the tablet core, as one embodiment.

As one of the embodiments of the invention, the oxycodone hydrochloride sustained release tablet also comprises a film coating which has good water solubility, can be rapidly dissolved in aqueous solution, and does not influence the dissolution and absorption of the drug. The high-temperature curing agent has good thermal stability, does not change quality in the high-temperature curing process, and can protect the tablet core from deformation. The coating materials include, but are not limited to, gastric-soluble film coating materials, and the specific type can be determined by one skilled in the art based on the present disclosure and in combination with common knowledge in the art.

As one of the embodiments of the invention, a layer of controlled release film coating can be coated on the outer layer of the tablet core, so that the release of the medicine can be regulated and controlled, and the hard inert material can protect the tablet core, prevent the physical and chemical damages of the tablet core from the outside and reduce the abuse condition of the medicine. The controlled release film coating is coated with a film coating material, the film material can be gastric-soluble film coating material, the weight gain of the film coating is 1.0% -8.0% of the weight of the tablet core, preferably 3.0% -5.0%, and the weight gain is exemplified as 1%, 2%, 3%, 4%, 5%, 6%, 7% or 8%.

Film coating techniques are well known to those skilled in the art, and have the advantages of mature process route, controllable quality and no influence on the release of the drug in vivo and in vitro.

The oxycodone hydrochloride sustained release tablet of the invention can be various tablet shapes commonly used in the field, and can be selected from round or abnormal tablet, and the shape of the tablet is on the premise of not influencing the drug release and not producing release residues.

The invention provides a preparation method for preparing the oxycodone hydrochloride osmotic pump sustained release tablet, which comprises the following steps:

1) Mixing the dry powder;

2) Tabletting;

3) Coating a controlled release film;

4) Film coating;

5) Curing;

6) And (5) cooling.

In the method of the present invention, as one of the embodiments, the method further comprises:

1) Mixing dry powder: uniformly mixing oxycodone hydrochloride and other auxiliary materials;

2) Tabletting: tabletting by a rotary tablet press, wherein the hardness is controlled to be 70-160N, preferably 80-150N, more preferably 90-140N, and the thickness of the control tablet is controlled to be 4-4.8 mm, preferably 4.1-4.5 mm;

3) And (3) coating a controlled release film: dissolving a film forming material and a pore-forming agent by using a controlled release film coating solvent, isolating and coating a tablet core by using high-efficiency coating equipment, controlling the coating temperature to be 20-50 ℃, and controlling the weight gain of the controlled release film coating to be 1.0-20.0%, preferably 3.0-12.0%, more preferably 6.0-10.0% of the weight of the tablet core; the controlled release film is coated, and then a laser perforating machine is used for perforating the upper surface and the lower surface of the tablet with a drug release hole, the pore diameter is controlled to be 0.2 mm-0.8 mm, preferably 0.4 mm-0.8 mm, more preferably 0.6 mm-0.8 mm (as an exemplary illustration, 0.4mm, 0.6mm, 0.7mm, etc.);

4) Film coating: dissolving the coating material by using a film coating solvent, carrying out isolation coating on the tablet core by adopting high-efficiency or fluidized bed coating equipment, controlling the coating temperature to be 20-50 ℃, and controlling the weight gain of the film coating to be 1-15% of the weight of the tablet core, preferably 1.0-8.0%, more preferably 3.0-6.0%, and even more preferably 3.0-5.0%;

5) Curing: curing the film-coated tablets by a drying oven or a coating pot, wherein the curing temperature is controlled to be 60-90 ℃, and preferably 70-80 ℃; the curing time is 1 to 8 hours, preferably 2 to 5 hours;

6) And (3) cooling: the cured film-coated tablet is cooled at normal temperature for 1 minute to 2 hours.

In the method of the present invention, as one embodiment, the step 1) further includes: oxycodone hydrochloride and half of polyoxyethylene and other auxiliary materials are poured into a wet mixing granulator, and the stirring speed is 30-200 rpm, preferably 50-180 rpm, more preferably 110-180 rpm (110 rpm, 120rpm, 130rpm, 140rpm, 150rpm, 160rpm, 170rpm and 180rpm are exemplified); the shearing speed is 300-4000 rpm, preferably 1000-3000 rpm, more preferably 2000-2800 rpm;2700rpm, mixing for 1min to 3min10min, preferably 2min to 6min, more preferably 2 to 5min; adding the rest polyoxyethylene, and stirring at 30-200 rpm, preferably 50-180 rpm, more preferably 110-180 rpm; the shearing speed is 300-4000 rpm, preferably 1000-3000 rpm, more preferably 2000-2800 rpm; mixing for 1min to 10min, preferably 2min to 6min, more preferably 2 to 5min.

As one embodiment, the solvent of the controlled release film coating in the step 3) is selected from the solvents used for the controlled release film coating, which are selected from methanol, ethanol, acetone, dichloromethane or water, or two or more of them; as one of the embodiments, it is preferable that acetone is a combination of two or more of the above solvents, and as one of the embodiments, the solvent is selected from a group consisting of a combination of acetone and ethanol, a combination of acetone and methanol, a mixture of acetone and water, a mixture of acetone and methylene chloride, and a mixture of methylene chloride and ethanol, in an amount of 50% to 90%, preferably 60.0% to 80.0%, more preferably 65.0% to 75.0% by weight of the controlled release film coating.

The invention creatively wraps the controlled release film coating layer on the outer layer of the matrix tablet core, adds a layer of physical barrier for the tablet core, does not change the original high hardness characteristic of the tablet core, greatly improves the cracking force of the tablet core, and further reduces the possibility of abuses after the tablet core is crushed.

The oxycodone hydrochloride sustained-release tablet comprises a tablet core, a controlled-release film coating and a film coating; the polyoxyethylene has a low melting point (65-70 ℃) and forms a high-hardness state after melting and cooling again, has good capability of preventing physical damage and chemical damage, and does not influence the slow release characteristic of the medicine. Therefore, the invention can effectively prevent the preparation from being abused by nasal inhalation after being crushed, or prevent the oxycodone hydrochloride in the preparation from being extracted, thereby reducing the abuse of oxycodone hydrochloride and improving the medication safety.

The invention further improves the preparation process of oxycodone hydrochloride sustained release tablets, and the prior art comprises the following steps:

1. because the tablet core contains a large amount of high polymer polyoxyethylene which is sticky when being heated, the coating pan is used for heating in the current technology to directly cure the tablet core, even if a large amount of magnesium stearate is added in the curing process, the rotating speed of the coating pan is increased, the serious sticky tablet or deformation can be generated as a result, and the product quality is influenced;

2. the inventor has found through experimental comparison that after the tablet core is coated by the controlled release film and the film coating, the phenomenon of sticking or deformation is avoided in the curing process, and the curing effect and release of the tablet core are not influenced by the film coating.

The test and comparison show that the sustained release tablet can realize more excellent curing effect.

The content of the invention not only can achieve more excellent abuse prevention effect than the prior art in the abuse prevention aspect, and improves the medication safety of the medicine; the invention is more feasible in the process aspect, and solves the problems of direct curing of the chip core, sticking and deformation.

Drawings

Fig. 1: examples 1-1 to 1-5 graph of drug release behavior;

Fig. 2: examples 2-1 to 2-3 graph of drug release behavior;

Fig. 3: examples 3-1 to 3-5 graph of drug release behavior;

Fig. 4: examples 4 to 6 show graphs of drug release behavior;

fig. 5: comparative examples 1 to 2 are graphs of drug release behavior;

Fig. 6: examples 1-3 compression resistance pictures;

fig. 7: example 3-3 compression resistance pictures;

fig. 8: comparative example 1 compression resistance picture;

fig. 9: comparative example 2 compression resistance picture;

Fig. 10: examples 1-3 blood concentration versus time graphs;

Fig. 11: plasma concentration-time graph

Detailed Description

The present invention is further illustrated by the following examples and experimental examples, but the present invention is not limited thereto.

Unless otherwise specified, the premix film coating materials used in the examples below were of the Colocorn company, gastric soluble type, opadry type II (commercially available). The following examples are only for illustration of the present invention and are not intended to limit the scope of the invention. Those skilled in the art can properly adjust the technical scheme without departing from the spirit and the main concept of the invention, and the technical scheme is within the protection scope of the invention.

Suitable modes of preparation include not only the following examples, but also tabletting, coating, etc. techniques conventional in the art can be used in the present invention.

EXAMPLE 1 curing conditions

1. Tablet core component (mg/P)

Mixing dry powder: the oxycodone hydrochloride, half amount of PEO 500 ten thousand and other auxiliary materials are poured into a wet mixing granulator, the stirring speed is 180rpm, the shearing speed is 2700rpm, and the mixing is carried out for 3min; adding the rest PEO 500 ten thousand, stirring at 180rpm, shearing at 2700rpm, and mixing for 5min;

Tabletting: tabletting by using a shallow concave die, putting a rotary tablet press for tabletting, controlling the hardness to be 80-150N, and controlling the tablet thickness to be 4.1-4.5 mm.

2. Controlled release film coating composition (%, w/w)

Dissolving cellulose acetate and polyethylene glycol (PEG 4000) with acetone, continuously coating tablet core with high-efficiency coating equipment at coating flow of about 100g/min and tablet bed temperature of about 30deg.C until the weight gain of the obtained controlled release film coating is 9% of that of tablet core.

After the controlled release film is coated, a laser perforating machine is used for perforating drug release holes on the upper surface and the lower surface of the tablet, and the aperture is 0.5mm;

3. Film coating

Preparing alcohol with proper concentration, and fully stirring and swelling the gastric soluble type Ophiopogon; continuously coating the tablet cores by using a high-efficiency coating pot; the solid content of the coating liquid is controlled at 10%, the coating flow is about 80g/min, the temperature of the tablet bed is about 30 ℃, and the weight gain of the obtained coating layer is 5% of that of the tablet core.

4. Curing conditions

Spreading the film-coated tablet on a screen, and curing according to the following conditions:

Lot number	Example 1-1	Examples 1 to 2	Examples 1 to 3	Examples 1 to 4	Examples 1 to 5
						Curing temperature/. Degree.C	60	65	70	75	80
Curing time/min	120	120	120	120	120
						Cooling time/min	120	120	120	120	120

Example 2 controlled Release film coating weight gain

1. Tablet core component (mg/P)

Tabletting: tabletting by using a shallow concave die, putting the tablets into a rotary tablet press for tabletting, controlling the hardness to be 10-20 kg/m ² and controlling the tablet thickness to be 4.1-4.5 mm.

2. Controlled release film coating composition (%, w/w)

Dissolving cellulose acetate and polyethylene glycol (PEG 4000) with acetone, continuously coating tablet core with high-efficiency coating equipment at coating flow of about 100g/min and tablet bed temperature of about 30deg.C,

The coating weight gain was controlled in the following range.

Lot number	Example 2-1	Example 2-2	Examples 2 to 3
				Coating weight gain/%	10	8	5

After the controlled release film is coated, a laser puncher is used for punching drug release holes on the upper surface and the lower surface of the tablet, and the aperture is 0.5mm;

3. Film coating

4. Curing conditions

Spreading the film-coated tablet on a screen, placing the screen on a 70 ℃ oven for curing for 120min (when the temperature of the oven reaches 70 ℃ and the timing is started), taking out the sample after curing is finished, and cooling the sample at room temperature for 120min.

Example 3 tablet core composition

1. Tablet core component (mg/P)

Component (%)/lot number	Example 3-1	Example 3-2	Examples 3 to 3	Examples 3 to 4	Examples 3 to 5
						Oxycodone hydrochloride	10	10	10	10	10
PEO 500 ten thousand	130	115	85	50	20
						PEO10 ten thousand	0	15	45	80	110
Hydroxypropyl cellulose	9	9	9	9	9
						Magnesium stearate	1	1	1	1	1
Total amount of	150	150	150	150	150

Mixing dry powder: the oxycodone hydrochloride, half of PEO 500 ten thousand, half of PEO10 ten thousand and other auxiliary materials are poured into a wet mixing granulator, the stirring speed is 180rpm, the shearing speed is 2700rpm, and the mixing is carried out for 3min; adding the rest PEO 500 ten thousand, stirring at 180rpm, shearing at 2700rpm, and mixing for 5min;

2. Controlled release film coating composition (%, w/w)

Dissolving cellulose acetate and polyethylene glycol (PEG 4000) with acetone, continuously coating tablet core with high-efficiency coating equipment at coating flow of about 100g/min and tablet bed temperature of about 30deg.C until the weight gain of the obtained controlled release film coating layer is 8% of that of tablet core. After coating the controlled release film, a laser puncher is used for punching drug release holes on the upper surface and the lower surface of the tablet, and the aperture is 0.5mm.

3. Film coating

Preparing alcohol with proper concentration, and fully stirring and swelling the gastric soluble type Ophiopogon; continuously coating the tablet cores by using a high-efficiency coating pot; the solid content of the coating liquid is controlled to be 10%, the coating flow is about 80g/min, the temperature of the tablet bed is about 30 ℃, and the coating weight gain is controlled to be 5%.

4. Curing conditions

Example 4

Tablet core component (mg/P)

2. The production process is the same as in example 3, wherein the upper and lower surfaces of the tablet are provided with drug release holes, and the aperture is 0.4mm;

3. Curing conditions were the same as in example 3.

Example 5

Tablet core component (mg/P)

2. The production process is the same as in example 3, wherein the upper and lower surfaces of the tablet are provided with drug release holes, and the aperture is 0.6mm;

3. Curing conditions were the same as in example 3.

Example 6

Tablet core component (mg/P)

2. The production process is the same as in example 3, wherein the upper and lower surfaces of the tablet are provided with drug release holes, and the aperture is 0.7mm;

3. Curing conditions were the same as in example 3.

4. The HPC used in this example is manufactured by Ashland, inc. and is available as HF.

Release rate and rate made according to the patent publication formula (see patent publication number US8894988, example 13.1)Consistent samples (comparative example 1) and(Production lot number DB421, 10mg specification) the preparation was subjected to release profile TEST and release uniformity investigation according to the TEST1 release conditions under the United states pharmacopoeia oxycodone hydrochloride sustained release tablet term.

Comparative example 1

Tablet core component (mg/P)

Mixing dry powder: the materials were poured into patterson Kelly "V" type mixers in the following order: half of the PEO 400 ten thousand, oxycodone hydrochloride, the remaining PEO 400 ten thousand, mix for 5min; adding magnesium stearate, and mixing for 1min.

Tabletting: tabletting by using a shallow concave die, and tabletting by using a rotary tablet press.

Curing: placing the tablet core into a 24 inch compu-lab coating pan, setting the rotation speed of the pan to 7rpm, setting the target temperature of the probe to 75 ℃, taking the temperature as a curing start point when the temperature reaches 70 ℃, and curing for 90min; at the end of curing, magnesium stearate is added to the moving tablet core as an anti-sticking agent. And after coating, cooling by ventilation at 21-25 ℃.

The weight of the coating is increased by 4 to 6 percent.

Comparative example 2

Product on the marketProduct information: specification 10mg/tablet, lot number: DB421.

Release degree measurement

The operation is as follows: the preparation method comprises the steps of taking the product by an HPLC method, taking 5ml of solution according to a device of oxycodone hydrochloride sustained release tablet TEST1 in USP pharmacopoeia of a release degree measurement method, taking artificial gastric juice (without enzyme) as a release medium 900ml, carrying out basket method and operation according to the method at the rotating speed of 100 revolutions per minute, taking 5ml of solution respectively after 1,2, 4, 6, 8 and 12 hours, filtering, and timely supplementing the release medium with the same temperature and the same volume. Detecting the release amount of the test solution under the 254nm wavelength of an HPLC method; and taking oxycodone hydrochloride as a reference substance, precisely weighing, adding phosphate buffer solution for dissolution and quantitatively diluting to prepare a solution containing about 0.1mg of oxycodone hydrochloride per 1ml, and measuring by the same method.

The release degree was evaluated according to the above release degree detection method. The release of each example is shown in Table 1; the release of each example is plotted, and the results of examples 1 to 6 are shown in fig. 1 to 4; comparative examples 1 to 2 are shown in fig. 5.

Table 1: data for release of each example (%)

Analysis and evaluation of experimental results:

The results of examples 1-1 to 1-5 show no significant difference in release, and the results show that the curing temperature has no significant effect on the release of the formulation.

The release degree results of examples 2-1 to 2-3 show that the release rate is reduced along with the increase of the weight of the controlled release film coating, and no obvious difference exists in the range of 5% -10% of the weight.

The release degree results of examples 3-1 to 3-5 show that when the PEO500 ten thousand accounts for more than 50% in the tablet core, the release rates are not significantly different; at a PEO500 w/w ratio of 20%, the release rate was significantly faster.

The release results of examples 4, 5 and 6 show that the change of the adhesive type in the tablet core has no significant effect on the release degree.

Compared with the samples prepared in comparative examples 1 and 2, the in-vitro release trend of the sample prepared in the examples is more gentle, the smooth release of the drug is facilitated, and the product in the invention can play a longer analgesic effect under the same dosage, so that the times and dosage of the drug can be reduced, the flux of the drug in the market can be reduced, and the difficulty of obtaining the product by an illegal way is greater, thereby reducing abuse. The medication compliance and the safety of patients can be improved while the medication times are reduced.

Tablet compression resistance test

Samples prepared in examples and comparative examples were subjected to a pressure of 400N with a DTKJ-63 pneumatic press (Windsor Automation technology Co., windsor, wenzhou) and a hammering frequency of 7 times, and the state of the samples after hammering, including the complete condition, the edge crack size, etc., was observed. The compression resistance results are shown in fig. 6 to 9.

Compared with comparative example 1 and comparative example 2, the integrity after hammering was better from the ground product (samples prepared in inventive examples 1-3, 3-3), the edge cracks were fewer, the cracks were smaller, and the damage to the ground product by hammering was smaller.

The self-grinding product is more difficult to crush and destroy, and the active substances in the self-grinding product are more difficult to extract, so that the abuse of drugs can be reduced to a greater extent. The invention is more effective in reducing abuse of the oral route than the comparative examples.

Pharmacokinetic studies

1.1 Instruments

An Analyst 1.5.1 workstation (AB SCIEX company, usa); DGU-20A3 on-line degasser, LC-20AD liquid chromatography infusion pump, SIL-20AC temperature controllable automatic sampler, CTO-20AC column incubator (Shimadzu corporation); AG-285 electronic analytical balance (Mettler-Tolyduo instruments Co., ltd.); genius 3-type automatic vortex machine, high-speed cryocentrifuge (samer-feishier scientific instruments ltd).

1.2 Pharmaceutical products and reagents

Test formulation: oxycodone hydrochloride sustained release tablets, the specification is as follows: 10 mg/tablet (prepared according to examples 1-3); reference formulation: (Purde developed and manufactured, specification: 10 mg/tablet); oxycodone hydrochloride control (China medicine biological products testing institute). Methanol (SIGMA company, chromatographic purity); acetonitrile (SIGMA, chromatography); ammonium acetate (aladine, chromatographic purity); water (double distilled water, homemade.)

1.3 Dosing regimen and blood sample collection

8 Healthy adult Beagle dogs have an average weight of 15.5kg (13.2-17.6 kg). Each preparation was orally administered 1 tablet, and venous blood was taken at 3ml for 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 12h after administration, and centrifuged at 5000rpm for 20min.

1.4 Chromatography, mass Spectrometry conditions

Chromatographic conditions: octyl silane bonded silica gel is used as a filler; 1.1 g/L1-sodium heptanesulfonate buffer (pH 2.0 adjusted with phosphoric acid): acetonitrile: methanol=700:100:200 is mobile phase; the detection wavelength is 2 to 30nm; column temperature is 40 ℃; sample injection amount: 40. Mu.L.

The results of the test formulations are shown in Table 2; the results of the reference formulations are shown in Table 3, and FIGS. 10-11. Its relative bioavailability is 123.5% + -14.2%. The 90% confidence interval of the pharmacokinetic parameter ln (AUC 0-t) of the tested preparation is in the range of 80% -125% of the reference preparation, the ln (Cmax) is in the range of 75% -133% of the reference preparation, and Tmax has no significant difference through non-parametric test, and the tested preparation is bioequivalent to the reference preparation.

TABLE 2 plasma concentration versus time curve for test formulations after single infusion of test formulations for Beagle dogs

TABLE 3 plasma concentration versus time curve for reference formulation after single infusion of test formulation for Beagle dogs

Claims

1. The oxycodone hydrochloride sustained release tablet is characterized by comprising a tablet core, a controlled release coating and a film coating, wherein the tablet core comprises the following components in percentage by weight:

the sum of the amounts of the above components is 100%, wherein,

The release regulator is selected from polyoxyethylene with a molecular weight of 500 ten thousand, or a combination of polyoxyethylene with a molecular weight of 10 ten thousand and polyoxyethylene with a molecular weight of 500 ten thousand, wherein the weight part ratio of the polyoxyethylene with a molecular weight of 10 ten thousand and the polyoxyethylene with a molecular weight of 500 ten thousand is 15:115-80:50;

The adhesive comprises hydroxypropyl cellulose, povidone, or hydroxypropyl methylcellulose, or a combination of two or more of the above;

the lubricant is magnesium stearate, micro silica gel, talcum powder, sodium laurylsulfate or a combination of two or more of the above materials;

the weight gain of the controlled release film coating is 5% -10% of the weight of the tablet core; the weight gain of the film coating is 1.0-8.0% of the weight of the tablet core;

the controlled release film coating comprises a film forming material, a pore-forming agent and a coating solvent;

the film forming material is cellulose acetate, and the dosage of the film forming material is 1.0-6.0% by weight of the controlled release film coating;

the pore-forming agent is PEG4000, and the dosage of the pore-forming agent is 0.1-20% based on the weight of the controlled release film coating;

The solvent used by the controlled release film coating is acetone, and the dosage is 80.0-95.0% based on the weight of the controlled release film coating;

The controlled release film coating is perforated by laser.

2. The sustained-release tablet according to claim 1, wherein the release modifier is selected from a combination of 10 ten thousand polyoxyethylene and 500 ten thousand polyoxyethylene, wherein the weight part ratio of 10 ten thousand polyoxyethylene to 500 ten thousand polyoxyethylene is 15:115, 45:85 or 80:50.

3. The sustained release tablet of claim 1, wherein the binder is hydroxypropyl cellulose.

4. The sustained-release tablet according to claim 1, wherein the lubricant is used in an amount of 0.1 to 4% by weight of the tablet core.

5. The sustained release tablet of claim 1, wherein the lubricant is magnesium stearate.

6. A method for preparing a sustained release tablet according to any one of claims 1 to 5, characterized in that the method comprises the steps of:

1) Mixing the dry powder;

2) Tabletting;

3) Coating a controlled release film coating and carrying out laser drilling;

4) Coating with a film;

5) Curing;

6) And (5) cooling.

7. The method of manufacturing according to claim 6, wherein the method further comprises:

2) Tabletting: tabletting by a rotary tabletting machine, controlling the hardness to be 80-150N and the thickness to be 4-4.8 mm;

3) And (3) coating a controlled release film: dissolving a film forming material and a pore-forming agent by using a controlled-release film coating solvent, isolating and coating a tablet core by using high-efficiency coating equipment, controlling the coating temperature to be 20-50 ℃, and controlling the weight gain of the controlled-release film coating to be 5-10% of the weight of the tablet core; coating the controlled release film, and punching a medicine release hole on the upper and lower surfaces of the tablet by a laser puncher, wherein the aperture is controlled to be 0.2-0.8 mm;

4) Film coating: dissolving the coating material by using a film coating solvent, isolating and coating the tablet core by using high-efficiency coating equipment, controlling the coating temperature to be 20-50 ℃, and controlling the weight gain of the film coating to be 1.0-8.0% of the weight of the tablet core;

5) Curing: curing the film-coated tablets by a drying oven or a coating pot, wherein the curing temperature is controlled to be 60-90 ℃; curing time is 1-8 hours;

6) And (3) cooling: the cured film-coated tablet is cooled at normal temperature.

8. The method of claim 7, wherein step 1) further comprises: the oxycodone hydrochloride and a half amount of polyoxyethylene and other auxiliary materials are poured into a wet mixing granulator, and the stirring speed is 30-200 rpm; the shearing rotating speed is 300-4000 rpm; mixing for 1-10 min; adding the rest polyoxyethylene, and stirring at 30-200 rpm; the shearing rotating speed is 300-4000 rpm; mixing for 1 min-10 min.

9. The sustained-release tablet according to claim 1, wherein the lubricant is used in an amount of 0.2 to 2% by weight of the tablet core.

10. The sustained release tablet of claim 1, wherein the weight gain of the controlled release film coating is between 6.0% and 10.0% by weight of the tablet core.

11. The sustained release tablet of claim 1, wherein the pore-forming agent is present in an amount of 0.5% to 15.0% by weight of the controlled release film coating.

12. The sustained release tablet of claim 11, wherein the pore-forming agent is present in an amount of from 0.5% to 5.0% by weight of the controlled release film coating.

13. The sustained release tablet of claim 11, wherein the porogen is present in an amount of 1.0% to 4.0% by weight of the controlled release film coating.

14. The sustained release tablet of claim 1, wherein the weight gain of the film coating is 3% to 6% by weight of the tablet core.

15. The sustained-release tablet according to claim 1, wherein the weight gain of the film coating is 3.0 to 5.0% of the weight of the tablet core.

16. The method of manufacturing according to claim 6, wherein the method further comprises:

2) Tabletting: tabletting by a rotary tabletting machine, controlling the hardness to be 90-140N and the thickness to be 4.1-4.5 mm;

3) And (3) coating a controlled release film: dissolving a film forming material and a pore-forming agent by using a controlled-release film coating solvent, isolating and coating a tablet core by using high-efficiency coating equipment, controlling the coating temperature to be 20-50 ℃, and controlling the weight gain of the controlled-release film coating to be 5-10% of the weight of the tablet core; coating the controlled release film, and punching a medicine release hole on the upper and lower surfaces of the tablet by a laser puncher, wherein the aperture is controlled to be 0.4-0.8 mm;

5) Curing: curing the film-coated tablets by a drying oven or a coating pot, wherein the curing temperature is controlled to be 70-80 ℃; curing time is 2-5 hours;

17. The method of manufacturing according to claim 6, wherein the method further comprises:

3) And (3) coating a controlled release film: dissolving a film forming material and a pore-forming agent by using a controlled-release film coating solvent, isolating and coating a tablet core by using high-efficiency coating equipment, controlling the coating temperature to be 20-50 ℃, and controlling the weight gain of the controlled-release film coating to be 6.0-10.0% of the weight of the tablet core; coating the controlled release film, and punching a medicine release hole on the upper and lower surfaces of the tablet by a laser puncher, wherein the aperture is controlled to be 0.6-0.8 mm;

4) Film coating: dissolving the coating material by using a film coating solvent, isolating and coating the tablet cores by using high-efficiency coating equipment, controlling the coating temperature to be 20-50 ℃, and controlling the weight gain of the film coating to be 3-6% of the weight of the tablet cores;

18. The method of claim 7, wherein step 1) further comprises: the oxycodone hydrochloride and a half amount of polyoxyethylene and other auxiliary materials are poured into a wet mixing granulator, and the stirring speed is 50-180 rpm; the shearing rotating speed is 1000-3000 rpm; mixing for 2-6 min; adding the rest polyoxyethylene, and stirring at 50-180 rpm; the shearing rotating speed is 1000-3000 rpm; mixing for 2-6 min.

19. The method of claim 7, wherein step 1) further comprises: the oxycodone hydrochloride and a half amount of polyoxyethylene and other auxiliary materials are poured into a wet mixing granulator, and the stirring speed is 110-180 rpm; the shearing rotating speed is 2000-2800 rpm; mixing for 2-5 min; adding the rest polyoxyethylene, and stirring at 110-180 rpm; the shearing rotating speed is 2000-2800 rpm; mixing for 2-5 min.